Although the etiologies of some secondary cataracts are becoming better understood and certain animal models show promise for elucidating the relationships between lens crystalline and hereditary cataract, little is known about the causes of congenital cataracts in humans. A better understanding of cataractogenesis will come through an understanding of the molecular components of the lens of the eye and the ways in which lesions of these components are manifested, structurally and functionally, as opacity of the lens. Currently, 5 different genetic congenital cataracts are being studied by linkage analysis, physical mapping, mutational screening, and expression in transgenic mice and in vitro. In addition, it is apparent that hereditary lesions that mimic or contribute additively to environmental stress known to cause cataracts might be candidate genes for causing age related cataracts. The work in this project is designed to specifically concentrate on congenital and complex hereditary cataracts and to take full advantage of molecular technology developed for linkage analysis and protein structural and functional studies. Lens crystallins comprise over 90% of the soluble protein of the lens and are heavily modified in most cataracts. The effects that specific modifications of beta and gamma-crystallin structure produce on crystallin functions, such as stability and formation of macromolecular aggregates, are being studied using SF9 cells transformed with bacculovirus vector containing coding sequences or normal and modified beta A3/A1- and B2-crystallin genes. Regions of the beta-crystallin molecule of special interest include the amino and carboxy terminal arms, the connecting peptide and the Greek key motifs of the core domains. In addition, the interactions of acidic and basic beta-crystallins are being studied.